Abstract
The authors aimed to investigate the association between sleep‐through morning surge (MS) in blood pressure (BP) and subclinical target organ damage in untreated hypertensives with different nocturnal dipping status. This cross‐sectional study included 1252 individuals who underwent anthropometric measurements, serum biochemistry evaluation, 24‐hour ambulatory blood pressure monitoring, echocardiography, and carotid ultrasonography. Left ventricular mass index, left atrial dimension, and carotid intima‐media thickness were evaluated. Participants were grouped according to nocturnal systolic BP dipping rate (388 dippers, 10%‐20%; 674 non‐dippers, 0%‐10%; 190 reverse dippers, <0%). Twenty‐two extreme dippers were excluded. While reverse dippers exhibited the most severe signs of damage, only dippers showed significant and positive correlation between MS and hypertension‐mediated organ damage (all P < .05), with significant area under the receiver operating characteristic curve for discriminating left ventricular hypertrophy (0.662), left atrial enlargement (0.604), and carotid intima‐media thickening (left, 0.758; right, 0.726; all P < .05). MS showed significant association with subclinical organ damage on both logistic and multiple linear regression analysis adjusted for age, sex, body mass index, smoking status, and alcohol consumption status, as well as for the levels of fasting blood glucose, uric acid, serum creatinine, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol, even when 24‐hour, daytime, nocturnal, and morning systolic BP were included (odds ratio >1 and P < .01 for all types of damage). Besides race, nocturnal dipping status might affect the role of MS in subclinical target organ damage, with a significant association only in dippers, independent of other systolic BP parameters. Dipping status might account for the discrepancies across previous reports.
Keywords: ambulatory blood pressure monitoring, dipping status, morning surge, target organ damage
1. INTRODUCTION
The clinical practice of hypertension management involves decision making based on absolute blood pressure (BP) levels, typically referring to the 24‐hour, daytime, and nocturnal averages, though complementary indicators such as diurnal BP changes, nocturnal dipping status, and BP variability are also considered. In recognition of the normal circadian evolution of BP, the commonly recommended cutoffs for distinguishing between normotension and hypertension are 135/85 and 120/70 mm Hg for daytime and nocturnal BP, respectively. Over the course of 24 hours, BP behavior frequently exhibits a dipping trend characterized by lower BP at nighttime than at daytime, with a normal dipping rate of 10%‐20% and with a peak in the early morning period, known as morning surge (MS).
Previous studies reported that blunted or diminished nocturnal BP dipping can translate into higher risk of organ damage, cardiovascular events, and mortality,1 even independent of office and 24‐hour BP.2, 3, 4, 5, 6 Additionally, numerous studies reported that, in terms of cardiovascular and mortality risk, extreme elevation of the MS is more impactful than extreme elevation of morning BP or 24‐hour SBP.7, 8, 9, 10 Moreover, even among the normotensive population, abnormally high MS (≥35 mm Hg) carries a fourfold residual risk for left ventricular hypertrophy (LVH; odds ratio [OR], 4.446; 95% confidence interval [95% CI], 1.793‐11.030)11 even after further adjustment for morning, 24‐hour, daytime, and nocturnal systolic BP (SBP). Taken together, these previous findings support the clinical importance of nocturnal BP dipping status and MS in addition to that of absolute BP values, which are well‐established parameters employed in BP management.
However, some studies have suggested that blunted, rather than exaggerated, MS accounts for adverse cardiovascular outcomes,12 and that increased cardiovascular risk might be attributed to a high prevalence of nocturnal BP reverse dipping among individuals with blunted MS.13 Conversely, Pierdomenico et al14, 15 reported that nocturnal BP dipping combined with MS > 23 mm Hg and non‐dipping are independent risk factors for heart failure and coronary events, while dipping combined with MS < 23 mm Hg was not a risk factor. Furthermore, blunted MS is always accompanied by reduced nocturnal dipping status or rate, and vice versa.8 In other words, the current body of literature contains contradictory results, suggesting that both exaggerated MS and blunted nocturnal BP can either decrease or increase cardiovascular risk. Additionally, few studies have focused on the role of MS in different dippers. In the present study, we aimed to clarify the effect of nocturnal BP dipping status on the association between MS and subclinical target organ damage indexes including left ventricular mass index (LVMI), left atrial dimension (LAD), and carotid intima‐media thickness (cIMT) in untreated hypertensives.
2. METHODS
2.1. Participants
Hypertensive individuals who underwent 24‐hour ambulatory BP monitoring (ABPM) at the inpatient or outpatient departments of West China Hospital between January and December 2015 were eligible to participate, provided that they simultaneously fulfilled the following criteria: (a) Chinese nationality, adult age, recent diagnosis of hypertension, and no prior antihypertensive therapy; (b) elevated ABPM parameters,16 including mean 24‐hour BP ≥ 130/80 mm Hg, and/or mean daytime BP ≥ 135/85 mm Hg, and/or mean nocturnal BP ≥ 120/70 mm Hg. The exclusion criteria were as follows: (a) definite secondary hypertension associated with renal failure, nephrotic syndrome, primary aldosteronism, etc; (b) symptomatic heart failure or ejection fraction <50% on echocardiography; (c) definite cardiomyopathy or valvular heart disease; (d) history of atrial fibrillation; (e) serum creatinine levels ≥260 μmol/L or undergoing regular hemodialysis; (f) aspartate aminotransferase/alanine aminotransferase levels more than twofold above the normal upper limit; (g) self‐reported history of hyperthyroidism; (h) working nights or extremely irregular schedules, going to bed after 23:00 hours or rising before 5:00 hours; and (i) history of Parkinson's disease. The Medical Ethics Committee of the West China Hospital of Sichuan University approved the study design and all procedures involved. All individuals provided written informed consent to participate in the study and undergo evaluation.
2.2. Collection of demographic, anthropometric, and laboratory data
Standardized questionnaires were administered to eligible individuals in order to collect demographic information concerning age, sex, alcohol consumption, tobacco smoking, and disease history. Height and weight were assessed using the standard approach. Venous blood was drawn in the morning after an 8‐hour fast to evaluate the levels of fasting blood glucose and the serum levels of lipids, liver enzymes, creatinine, urea nitrogen, cystatin C, and uric acid.
2.3. ABPM parameters and dipping status
A 24‐hour ABPM device (90217; Spacelabs Healthcare) with an appropriately sized cuff was used to collect 24‐hour BP data. The participants were instructed to continue their regular activity and sleep schedule, but to remain motionless during BP measurement. BP data were measured every 20 minutes from 6:00 hours to 22:00 hours and every 30 minutes from 22:00 hours to 6:00 hours on the next day. A routine diary card was given to every participant to record the time when they went to bed and woke up. To be considered satisfactory, ABPM data had to satisfy the following conditions16, 17: (a) >70% valid readings; (b) at least 20 daytime and 7 nighttime valid readings; and (c) at least one valid reading every hour. Daytime BP was defined as the mean of BP values collected from 6:00 hours to 22:00 hours, while nocturnal BP was defined as the mean of BP values collected from 22:00 hours to 6:00 hours the next day. Morning BP was defined as the mean of BP values collected within 2 hours after waking up. MS was defined as the sleep‐through morning BP surge, calculated as the difference between morning BP and the lowest nighttime BP, which was the average between the lowest BP reading and the two readings immediately preceding and after the lowest reading. The nocturnal BP dipping rate was calculated based on SBP as follows: 100 × (daytime − nighttime SBP)/(daytime SBP). Further, nocturnal dipping status was classified into four categories according to the dipping rate16, 17: (a) dipper (≥10% but < 20%); (b) non‐dipper (≥0% but < 10%); (c) extreme dipper (≥20%); and (d) reverse dipper (<0%).
2.4. Transthoracic echocardiography and carotid ultrasonography measurements
Transthoracic echocardiography was conducted by experienced operators who performed at least 1000 such procedures annually and who were blinded to the participants' ABPM results. The measurement was conducted using the GE Vivid E9 color Doppler ultrasound detector with an M5S probe (GE Healthcare). The linear method with M‐mode tracing was used to measure the end‐diastolic interventricular septal wall thickness (IVS), left ventricular end‐diastolic diameter (LVID), and end‐diastolic posterior wall thickness (PWT). LAD was defined as the anteroposterior dimension of the left atrium, measured in the parasternal long‐axis view. The left ventricular mass (LVM; in grams) was then calculated according to the following formula18: LVM = 0.8 × 1.04 × [(IVS + LVID+PWT)3 − LVID3] + 0.6. The following LVMIs were defined: (a) LVMI1 = LVM/(body surface area, m2); (b) LVMI2 = LVM/(height2.7, m2.7). Then, LVH was defined in participants who fulfilled any of the following conditions16, 18: (a) LVMI1 > 115 g/m2 or LVMI2 > 50 g/m2.7 for men; (b) LVMI1 > 95 g/m2 or LVMI2 > 47 g/m2.7 for women. Left atrial enlargement was defined in participants with LAD values >40 mm for men and >38 mm for women.18 The measurement of cIMT was conducted by an experienced sonographer using a Philips CX50 color Doppler ultrasound system, an L12‐3 probe, and the QLab software (Phillips Medical Systems). A cIMT >0.9 mm was considered to indicate carotid intima‐media thickening.16
2.5. Statistical analysis
The Kolmogorov‐Smirnov test was used to test the normality of data distribution. Continuous variables were reported as mean ± standard deviation for normally distributed data. Categorical variables were expressed as frequency or percentage. Differences among more than two groups were evaluated using one‐way analysis of variance (ANOVA). The chi‐squared test was used to test intergroup differences in frequency. Pearson's correlation analyses were used to assess the correlations between two variables with normal distribution. Receiver operating characteristic curves were plotted, and the area under the curve was calculated as a measure of the diagnostic performance of MS as a marker of LVH, left atrial enlargement, and carotid intima‐media thickening. The association between MS and target organ damage was ascertained by conducting multiple linear regression analysis and logistic regression analysis. Statistical analyses were conducted using SPSS version 23.0 for Windows (IBM Corp., Armonk, NY, USA), and statistical significance was set at P ≤ .05.
3. RESULTS
3.1. Baseline characteristics
A total of 1252 individuals (388 dippers, 674 non‐dippers, and 190 reverse dippers) were enrolled consecutively in our study (age, 54.8 ± 14.3 years; male sex, 48.7%). As the number of extreme dippers was very low (n = 22), we excluded this group from the analysis, as any conclusions based on such a limited sample size would not be adequately powered. The MS values exhibited a normal distribution for each dipping status (Figure 1). Compared with dippers and non‐dippers, reverse dippers were older, had higher fasting blood glucose levels, and were more likely to smoke (Table 1). The groups did not differ significantly in terms of 24‐hour BP or morning SBP (Table 1, Figure 2). While nocturnal BP varied substantially across the groups, the intergroup variation of daytime BP and morning diastolic BP was less pronounced. The most severe signs of organ damage were observed in reverse dippers, whereas dippers and non‐dippers did not differ in terms of important parameters such as cystatin C levels, LAD, and LVMI1.
Figure 1.
Frequency distribution of values for morning blood pressure surge according to dipping status. Data are shown for dippers (left), non‐dippers (middle), and reverse dippers (right). The Kolmogorov‐Smirnov test was used to test the normality of data distribution
Table 1.
Demographic and clinical characteristics according to dipping status
| Characteristic | All (n = 1252) | Dipper (n = 388) | Non‐dipper (n = 674) | Reverse dipper (n = 190) | P‐value |
|---|---|---|---|---|---|
| Age, y | 54.8 ± 14.3 | 52.8 ± 14.1 | 54.2 ± 14.2 | 60.8 ± 13.5 | <.01*+ |
| Male sex | 1252 (48.7) | 196 (50.5) | 326 (48.4) | 88 (46.3) | .615 |
| Smoker | 181 (14.5) | 54 (13.9) | 83 (12.3) | 44 (23.2) | .001*+ |
| Drinker | 182 (14.5) | 63 (16.2) | 88 (13.1) | 31 (16.3) | .276 |
| Diabetes mellitus | 192 (15.3) | 55 (14.2) | 91 (13.5) | 46 (24.2) | .001*+ |
| BMI, kg/m2 | 24.4 ± 4.0 | 24.6 ± 4.1 | 24.4 ± 4.0 | 24.0 ± 3.8 | .433 |
| FBG, mmol/L | 6.01 ± 1.75 | 5.88 ± 1.57 | 5.96 ± 1.63 | 6.45 ± 2.34 | .002*+ |
| BUN, mmol/L | 5.56 ± 2.23 | 5.51 ± 1.98 | 5.49 ± 2.47 | 5.92 ± 1.71 | .105 |
| CREA, µmol/L | 73.8 ± 22.4 | 74.7 ± 26.9 | 73.5 ± 19.6 | 72.8 ± 22.0 | .633 |
| eGFR, mL/min/1.73 m2 | 88.7 ± 21.2 | 88.7 ± 19.1 | 88.7 ± 21.1 | 89.1 ± 25.7 | .969 |
| Cys‐C, mg/L | 0.95 ± 0.24 | 0.93 ± 0.25 | 0.94 ± 0.22 | 1.03 ± 0.27 | <.01*+ |
| URIC, µmol/L | 336 ± 90 | 340 ± 93 | 334 ± 87 | 335 ± 97 | .652 |
| TG, mmol/L | 1.66 ± 1.18 | 1.69 ± 1.05 | 1.68 ± 1.25 | 1.57 ± 1.18 | .555 |
| TC, mmol/L | 4.78 ± 1.06 | 4.74 ± 0.96 | 4.82 ± 1.08 | 4.72 ± 1.13 | .411 |
| HDL‐C, mmol/L | 1.43 ± 0.41 | 1.41 ± 0.39 | 1.43 ± 0.40 | 1.46 ± 0.49 | .499 |
| LDL‐C, mmol/L | 2.64 ± 0.79 | 2.64 ± 0.78 | 2.66 ± 0.79 | 2.59 ± 0.84 | .660 |
| Na+, mmol/L | 141.4 ± 2.8 | 141.4 ± 2.7 | 141.5 ± 2.8 | 140.9 ± 3.2 | .228 |
| K+, mmol/L | 4.06 ± 0.36 | 4.06 ± 0.37 | 4.06 ± 0.35 | 4.04 ± 0.39 | .822 |
| 24‐h SBP, mm Hg | 125.8 ± 14.5 | 125.8 ± 13.8 | 125.6 ± 15.0 | 126.3 ± 14.4 | .861 |
| 24‐h DBP, mm Hg | 79.0 ± 10.2 | 79.1 ± 9.5 | 79.2 ± 10.5 | 77.8 ± 10.7 | .206 |
| 24‐h PP, mm Hg | 46.8 ± 10.4 | 46.6 ± 10.1 | 46.4 ± 10.0 | 48.3 ± 11.4 | .082 |
| 24‐h PR, beats/min | 72.8 ± 9.5 | 72.9 ± 8.7 | 72.8 ± 9.0 | 72.5 ± 12.2 | .870 |
| Daytime SBP, mm Hg | 127.0 ± 14.7 | 128.5 ± 14.1 | 126.7 ± 15.1 | 125.3 ± 14.3 | .031•* |
| Daytime DBP, mm Hg | 79.9 ± 10.4 | 80.9 ± 9.7 | 80.1 ± 10.6 | 77.4 ± 10.7 | .001*+ |
| Daytime PP, mm Hg | 47.1 ± 10.5 | 47.5 ± 10.4 | 46.7 ± 10.4 | 48.0 ± 11.1 | .222 |
| Daytime PR, beats/min | 74.3 ± 9.7 | 74.5 ± 9.0 | 74.3 ± 9.3 | 73.7 ± 12.4 | .606 |
| Nocturnal SBP, mm Hg | 119.1 ± 15.9 | 111.0 ± 12.7 | 120.1 ± 15.0 | 131.7 ± 15.9 | <.01•*+ |
| Nocturnal DBP, mm Hg | 73.6 ± 10.7 | 69.0 ± 9.1 | 74.6 ± 10.5 | 79.1 ± 11.1 | <.01•*+ |
| Nocturnal PP, mm Hg | 45.6 ± 10.9 | 42.0 ± 9.2 | 45.6 ± 10.2 | 52.6 ± 12.8 | <.01•*+ |
| Nocturnal PR, beats/min | 64.1 ± 9.2 | 63.4 ± 8.5 | 64.1 ± 8.7 | 65.8 ± 11.8 | .014*+ |
| Morning SBP, mm Hg | 127.4 ± 16.3 | 128.8 ± 15.8 | 127.0 ± 16.7 | 126.0 ± 16.0 | .102 |
| Morning DBP, mm Hg | 81.0 ± 11.5 | 81.8 ± 10.8 | 81.1 ± 11.9 | 78.9 ± 11.2 | .013*+ |
| Morning PP, mm Hg | 23.2 ± 5.8 | 23.5 ± 5.8 | 22.9 ± 5.8 | 23.5 ± 6.0 | .231 |
| Morning PR, beats/min | 75.9 ± 12.2 | 76.6 ± 11.7 | 75.3 ± 11.8 | 76.3 ± 14.2 | .243 |
| MS, mm Hg | 21.7 ± 13.0 | 31.2 ± 10.0 | 19.9 ± 10.2 | 8.5 ± 13.3 | <.01•*+ |
| Dipping rate, % | 6.2 ± 6.9 | 13.6 ± 2.6 | 5.2 ± 2.9 | ‐5.2 ± 5.0 | <.01•*+ |
| LAD, mm | 36.7 ± 4.9 | 36.7 ± 4.8 | 36.4 ± 4.8 | 37.9 ± 5.0 | .013*+ |
| LVMI1, g/m2 | 88.9 ± 19.8 | 86.1 ± 18.3 | 89.2 ± 18.7 | 93.3 ± 24.6 | .037* |
| LVMI2, g/m2.7 | 39.8 ± 10.0 | 38.8 ± 9.5 | 40.0 ± 9.7 | 41.1 ± 11.7 | .263 |
| Left cIMT, mm | 0.75 ± 0.18 | 0.75 ± 0.17 | 0.74 ± 0.18 | 0.78 ± 0.18 | .335 |
| Right cIMT, mm | 0.73 ± 0.17 | 0.72 ± 0.17 | 0.73 ± 0.16 | 0.75 ± 0.17 | .463 |
Data are shown as mean ± standard deviation or frequency (percentage).
Statistical significance: • for dipper vs non‐dipper; * for dipper vs reverse dipper; + for non‐dipper vs reverse dipper.
Abbreviations: BMI, body mass index; BUN, serum urea nitrogen; cIMT, carotid intima‐media thickness, measured on the left and right side of the common carotid artery; CREA, serum creatinine; Cys‐C, cystatin C; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; HDL‐C, high‐density lipoprotein cholesterol; K+, serum potassium; LAD, left atrial dimension; LDL‐C, low‐density lipoprotein cholesterol; LVMI, left ventricular mass index; MS, morning surge; Na+, serum sodium; PP, pulse pressure; PR, pulse rate; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; URIC, uric acid.
Figure 2.
Circadian fluctuation of blood pressure according to dipping status. Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure
3.2. MS as a marker of target organ damage
All organ damage indexes other than right cIMT exhibited significant and positive correlation with MS in dippers (all P < .05), whereas no significant correlations were noted in non‐dippers or reverse dippers (all P > .05; Table 2). Similarly, MS had significant diagnostic performance for LVH, left atrial enlargement, and carotid intima‐media thickening in dippers (all P < .05) but not in non‐dippers or reverse dippers (all P > .05; Table 3).
Table 2.
Correlation between morning surge in blood pressure and target organ damage according to dipping status
| LVMI1 | LVMI2 | LAD | Left cIMT | Right cIMT | |
|---|---|---|---|---|---|
| Dipper | 0.356** | 0.407** | 0.168* | 0.233** | 0.169 |
| Non‐dipper | 0.025 | 0.040 | 0.024 | 0.098 | 0.119 |
| Reverse dipper | 0.020 | 0.060 | 0.111 | −0.182 | −0.166 |
The data were obtained via Pearson's correlation analysis.
Abbreviations: cIMT, carotid intima‐media thickness, measured on the left and right side of the common carotid artery; LAD, left atrial dimension; LVMI, left ventricular mass index.
P < .05.
P < .01.
Table 3.
Morning surge in blood pressure as a predictor of target organ damage according to dipping status
| Type of damage | Dipper | Non‐dipper | Reverse dipper |
|---|---|---|---|
| LVH | 0.662 (0.554‐0.769)** | 0.497 (0.411‐0.583) | 0.536 (0.398‐0.674) |
| LAE | 0.604 (0.525‐0.682)* | 0.513 (0.453‐0.573) | 0.524 (0.420‐0.628) |
| Left cIM thickening | 0.758 (0.636‐0.880)** | 0.522 (0.382‐0.661) | 0.399 (0.218‐0.580) |
| Right cIM thickening | 0.726 (0.557‐0.894)* | 0.620 (0.487‐0.752) | 0.376 (0.190‐0.561) |
Data were obtained using receiver operating characteristic analysis. The area under the curve is expressed as mean (95% confidence interval).
Abbreviations: cIM, carotid intima media; LAE, left atrial enlargement; LVH, left ventricular hypertrophy.
P < .05.
P < .01.
3.3. Makers of target organ damage in reverse dippers
In reverse dippers, the 24‐hour peak in BP was noted at night (Figure 2). Therefore, we examined the association of nocturnal BP and nocturnal BP surge with target organ damage. Upon defining dynamic nocturnal surge as the average peak nocturnal SBP minus the lowest nocturnal SBP,19 we found significant correlation between nocturnal SBP and all organ damage indexes in reverse dippers (all P < .05), whereas nocturnal diastolic BP and nocturnal surge showed no such associations (all P > .05; Table S1). Similarly, only nocturnal SBP (and not nocturnal diastolic BP or nocturnal surge) was a significant predictor of target organ damage (Table S2).
3.4. Association between MS and target organ damage on multiple linear regression analysis
In Model 1, age, sex, body mass index, smoking status, and alcohol consumption status, as well as the levels of fasting blood glucose, uric acid, creatinine, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol, were included as covariates, whereas target organ damage indexes were set as dependent variables. Upon stepwise selection, MS entered all models in dippers, confirming a significant association between MS and target organ damage (β‐values: .688, .363, .132, and .005 for LVMI1, LVMI2, LAD, and left cIMT, respectively; all P < .05), which was independent of 24‐hour, daytime, nocturnal, and morning SBP (all P < .05). However, no significant relationship between MS and target organ damage was found in non‐dippers or reverse dippers (all P > .05; Table 4).
Table 4.
Multiple linear regression analysis of the association between the morning surge in blood pressure and target organ damage indexes according to dipping status
| Index | Model 1 | Model 2 | ||
|---|---|---|---|---|
| β | P‐value | β | P‐value | |
| LVMI1 | ||||
| Dipper | .688 | <.01** | .688 | <.01** |
| Non‐dipper | .035 | .614 | .014 | .839 |
| Reverse dipper | .050 | .679 | −.186 | .139 |
| LVMI2 | ||||
| Dipper | .363 | <.01** | .363 | <.01** |
| Non‐dipper | .047 | .457 | −.068 | .319 |
| Reverse dipper | .073 | .520 | −.066 | .568 |
| LAD | ||||
| Dipper | .132 | .002** | .132 | .002** |
| Non‐dipper | −.080 | .215 | −.076 | .224 |
| Reverse dipper | .040 | .723 | .067 | .515 |
| Left cIMT | ||||
| Dipper | .005 | .010* | .005 | .010* |
| Non‐dipper | .000 | .997 | .000 | .997 |
| Reverse dipper | −.079 | .540 | −.039 | .740 |
| Right cIMT | ||||
| Dipper | .164 | .169 | .164 | .169 |
| Non‐dipper | .174 | .065 | .174 | .065 |
| Reverse dipper | −.112 | .404 | −.112 | .404 |
Stepwise selection was used for all models. Model 1 included the following as covariates: age, sex, body mass index, smoking status, and alcohol consumption status, as well as the levels of fasting blood glucose, uric acid, creatinine, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol. Model 2 included all covariates from Model 1 plus 24‐hour, daytime, nocturnal, and morning systolic blood pressure.
P < .05.
P < .01.
3.5. Association between MS and target organ damage on logistic regression analysis
On univariate logistic regression analysis, MS entered all models in dippers (OR: 1.060, 1.035, and 1.097, respectively, for LVH, left atrial enlargement, and carotid intima‐media thickening on the left side; all P < .05) but not in non‐dippers or reverse dippers (all P > .05; Table 5). Similar results were obtained after including as covariates the age, sex, body mass index, smoking status, and alcohol consumption status, as well as the levels of fasting blood glucose, uric acid, creatinine, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol.
Table 5.
Logistic regression analysis of the association between the morning surge in blood pressure and target organ damage according to dipping status
| Type of damage | Model 1 | Model 2 | ||
|---|---|---|---|---|
| OR (95% CI) | P‐value | OR (95% CI) | P‐value | |
| LVH | ||||
| Dipper | 1.060 (1.015‐1.107) | .008** | 1.060 (1.000‐1.123) | .048* |
| Non‐dipper | 0.997 (0.967‐1.029) | .997 | 1.013 (0.973‐1.055) | .525 |
| Reverse dipper | 1.011 (0.973‐1.050) | .575 | 0.996 (0.928‐1.069) | .911 |
| LAE | ||||
| Dipper | 1.035 (1.006‐1.065) | .019* | 1.089 (1.037‐1.145) | .001** |
| Non‐dipper | 1.007 (0.987‐1.027) | .513 | 0.977 (0.942‐1.013) | .204 |
| Reverse dipper | 1.009 (0.980‐1.038) | .561 | 0.994 (0.941‐1.052) | .846 |
| Left cIM thickening | ||||
| Dipper | 1.097 (1.030‐1.169) | .004** | 1.114 (1.021‐1.215) | .015* |
| Non‐dipper | 1.020 (0.975‐1.067) | .392 | 0.856 (0.717‐1.022) | .086 |
| Reverse dipper | 0.968 (0.920‐1.019) | .216 | 0.907 (0.725‐1.133) | .389 |
| Right cIM thickening | ||||
| Dipper | 1.061 (0.990‐1.136) | .095 | 1.279 (0.950‐1.722) | .105 |
| Non‐dipper | 1.053 (0.997‐1.113) | .064 | 1.027 (0.967‐1.091) | .390 |
| Reverse dipper | 0.972 (0.914‐1.032) | .350 | 0.961 (0.887‐1.041) | .329 |
Model 1 was based on univariate logistic regression analysis. Model 2 included the following as covariates: age, sex, body mass index, smoking status, and alcohol consumption status, as well as the levels of fasting blood glucose, uric acid, creatinine, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol.
Abbreviations: 95% CI, 95% confidence interval; cIM, carotid intima media; LAE, left atrial enlargement; LVH, left ventricular hypertrophy; OR, odds ratio.
P < .05.
P < .01.
4. DISCUSSION
The present findings suggest that dipping status might affect the association between MS and subclinical target organ damage. Unlike non‐dippers and reverse dippers, dippers exhibited significant and positive associations between MS and target organ damage, and this relationship was independent of other BP‐based parameters including 24‐hour, daytime, nocturnal, and morning SBP.
It is obviously contradictory that exaggerated and blunted MS would both lead to adverse cardiovascular outcomes, as suggested in the current body of literature.7, 8, 9, 10, 12, 13, 20 There may be several reasons for the discrepant findings. First, nocturnal BP and non‐dipping status might be major confounders of the relationship between MS and cardiovascular outcomes in the general population, and previous studies did not adjust for such confounders.12, 13, 20 Second, although MS can be negative (ie, in reverse dippers) and may be not applicable to all populations, previous studies on MS did not exclude reverse dippers from the analyses. Third, MS may not be a robust marker of subclinical target organ damage, and its effect on cardiovascular risk might vary with dipping status and race. It is likely that the reason for such contradictory findings reported in the literature is related to differences in dipping status distribution across study samples.
The powerful association between MS and cardiovascular events was first described by Kario et al7 in a study with an average follow‐up of 41 months. Later, Li et al8 reported findings from the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study, which included 5464 hypertensive patients followed up for an average of 11.4 years. Neither of these previous studies reported the dipping status distribution in their sample. The average nocturnal BP dipping rates reported by Kario et al7 were 18.8% in the MS group (53 participants) and 12.4% in the non‐MS group (466 participants), whereas those reported by Yan Li et al8 were 18.3% in participants with MS < 37 mm Hg and 13.3% in participants with MS ≥ 37 mm Hg. The association between MS and increased risk of cerebral hemorrhage (relative risk, 4; 95% CI, 1.08‐14.63) was also supported by findings from the Ohasama study, in which the average nocturnal BP decline rate was about 13% in the general population,10 compared to 13.6% in dippers, 5.2% in non‐dippers, and −5.2% in reverse dippers evaluated in the present study. Taken together, these findings indirectly suggest that the population samples of previous studies consisted mainly of dippers.
Ethnic factors may also affect the association between MS and cardiovascular risk. Hoshide et al21 demonstrated that, compared to Europeans, Japanese persons had a much larger MS and higher morning BP. By contrast, a study by Bombelli et al20 in a white population found a weak positive association of morning SBP surge with the risk of cardiovascular and all‐cause death, but this association disappeared after adjustment for confounders. By excluding non‐dippers and reverse dippers with blunted or diminished MS, previous studies could not ascertain the net association between MS and cardiovascular risk, whereas the present study revealed such an association only in dippers and not in non‐dippers or reverse dippers.
It is notable that the incidence of cardiovascular events including ischemic stroke22 and coronary events23 is higher in the early morning period. Other studies confirmed the importance of BP parameters measured in the early morning. The Japan Morning Surge‐Home Blood Pressure (J‐HOP) study24 found that morning SBP was closely associated with the urine albumin‐to‐creatinine ratio and the pulse‐wave velocity. Kario et al25 found that morning hypertension was the strongest independent predictor of stroke among other BP parameters including office, 24‐hour, awake, sleep, evening, and pre‐awake BP. Furthermore, in the Home blood pressure measurement with Olmesartan‐Naïve patients to Establish Standard Target blood pressure (HONEST) study,26 home morning BP was a strong predictor of coronary artery disease and stroke events, with hazard ratios of 6.10 (95% CI, 2.85‐12.68) and 6.24 (95% CI, 2.82‐13.84), respectively. Based on this evidence, many guidelines and reviews focus on morning BP as the object of BP management.16, 27, 28, 29, 30 However, there has been increasing interest in nocturnal BP as the BP parameter most closely related to cardiovascular risk.19, 31, 32, 33, 34 As recommended by Kario, controlling morning BP is only the first step toward perfect 24‐hour BP control and should be followed by the control of nocturnal hypertension.28, 30 In other words, to restore the normal circadian rhythm of BP, reverse nocturnal BP dipping should be canceled (ie, transitioning from reverse dipper to non‐dipper status). However, Ye et al11 revealed that abnormal MS is associated with cardiovascular risk even if morning, daytime, and nocturnal BP are normal. Thus, MS control is expected to represent the final step in achieving perfect 24‐hour BP control.
It is important to note that, whereas nocturnal BP and MS can be evaluated only via regular ABPM, morning BP is a more convenient hallmark for BP control because it can be measured not only via ABPM but also via daily home BP monitoring (HBPM) during daytime, while the person is awake. The present study does not highlight the importance of MS over that of reverse dipping or non‐dipping status, but rather suggests that BP should be managed in a stepwise manner, by first correcting dipping status (by controlling morning, daytime, and nocturnal BP) and then controlling MS.
Several limitations of the present study should be considered. First, this cross‐sectional study was conducted in an untreated population and thus could not assess the confounding effect of antihypertensive drugs, which is expected to play a role in other populations. Further studies are needed to understand whether the impact of MS varies with race. Second, we could not clarify the association between MS and subclinical target organ damage in extreme dippers because of the limited sample size. Nevertheless, a prospective study by Kario et al35 reported that extreme dipping combined with exaggerated MS was associated with an increased risk of clinical stroke events (vs the risk in dippers). Third, while MS can be calculated by two algorithms (sleep‐through MS and pre‐awakening MS), our study only focused on sleep‐through MS. Further research is warranted to clarify the association between pre‐awakening MS and target organ damage. Finally, our present conclusions should be validated in prospective and adequately powered studies on long‐term cardiovascular outcomes.
To conclude, we found that nocturnal BP dipping status might affect the association between MS and subclinical target organ damage, with a significant and positive association noted only in dippers (not in non‐dippers or reverse dippers), and independent of other BP parameters including 24‐hour, daytime, nocturnal, and morning SBP. This effect of nocturnal BP dipping status may account for the wide discrepancies in the results reported to date. Taken together with previous observations, our present findings support a three‐step strategy for perfect 24‐hour BP control in which the control of morning BP by daily HBPM should be the first step, followed by the control of nocturnal hypertension, and MS control as the final target, in which regular ambulatory BP monitoring is key.
CONFLICT OF INTEREST
The authors have no competing interests to declare.
AUTHOR CONTRIBUTIONS
All authors have approved the final version of the manuscript, and specific contributions of each co‐author to the article are as follows: Shenzhen Gong MD: collected data, analyzed data, and wrote and revised the article. Kai Liu MD: collected data, analyzed data, and wrote and revised the article. Runyu Ye MD: collected data. Jiangbo Li MD: collected data. Changqiang Yang MD: collected data. Xiaoping Chen MD: raised questions and designed the study, analyzed data, gave constructive advise on data analysis and article writing, and submitted and revised the manuscript.
Supporting information
ACKNOWLEDGMENTS
Firstly, we wish to thank Dr Xiaoping Chen for the original idea and scientific study design. Secondly, Shenzhen Gong and Kai Liu have contributed to the study equally for data collection, data analysis, manuscript writing, and revising. Finally, we also thank other authors' for collecting data including Runyu Ye, Jiangbo Li, and Changqiang Yang.
Gong S, Liu K, Ye R, Li J, Yang C, Chen X. Nocturnal dipping status and the association of morning blood pressure surge with subclinical target organ damage in untreated hypertensives. J Clin Hypertens. 2019;21:1286–1294. 10.1111/jch.13641
Shenzhen Gong and Kai Liu contributed equally to this work.
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